Long-term cadmium exposure induces anemia in rats through hypoinduction of erythropoietin in the kidneys

Abstract

Cadmium (Cd), a highly toxic heavy metal, is distributed widely in the general environment of today. The characteristic clinical manifestations of chronic Cd intoxication include renal proximal tubular dysfunction, general osteomalacia with severe pains, and anemia. We have recently reported that the serum level of erythropoietin (EPO) remained low despite the severe anemia in patients with Itai-itai disease, the most severe form of chronic Cd intoxication. In order to prove that the anemia observed in chronic Cd intoxication arises from low production of EPO in the kidneys following the renal injury, we administered Cd to rats for a long period and performed the analysis of EPO mRNA inducibility in the kidneys. The rats administered Cd for 6 and 9 months showed anemia with low levels of plasma EPO as well as biochemical and histological renal tubular damage, and also hypoinduction of EPO mRNA in the kidneys. The results indicate that chronic Cd intoxication causes anemia by disturbing the EPO-production capacity of renal cells.

Alteration in the activity of oxidative enzymes in the tissues of male wistar albino rats exposed to cadmium

“…The inhibitory effect of Cd on the digestive and absorption enzymes may also account for the decreased feed efficiency observed in the Cd treated rats. The increased accumulation of Cd observed in the liver and kidney of Cd exposed rats is in consonance with earlier reports [16,21,22]. Examination of the cadmium levels in the liver of rats after both periods of exposure to cadmium shows that it was consistently higher than the level in kidney.…”

“…The decrease in weight gain of the rats is in consonance with previous reports on the effect of cadmium on weight gain of rats [16,17]. The decrease in weight gain and the corresponding increase in dry fecal output of the Cd trea ted rats is also consistent with previous reports on the inhibitory effect of Cd on digestive and absorption enzymes in rats [18][19][20].…”

“…Changes in organ/body weight ratio in rats administered Cd have also been observed by many workers. Horiguchi et al [16] observed hepatosplenomegaly and kidney swelling after subcutaneous administration of Cd in rats. Similarly, a Cd-induced increase in liver and spleen weight has also been observed by Tu et al [28].…”

“…subcutaneously, more was deposited in the liver than in the kidneys [16,23,24]. Experimental evidence also indicates that the transport and distribution of Cd to tissues is aided by metallothionein (MT) [25,26].…”

Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1α) and HIF-regulated genes

“…Several Fe(II)-dependent enzymes, such as the HIF-prolyl hydroxylase (PHD 1-3) and asparagine hydroxylase (FIH-1), regulate HIF-1α stability and activation. Numerous studies have shown that HIF-1α is not only regulated by oxygen tension, but also by various other stimuli, such as transition metals, which can mimic hypoxia to stabilize HIF-1α protein in cultured cells (Horiguchi et al, 1996;Oshiro et al, 1998;Chun et al, 2000;Hossain et al, 2000;Gao et al, 2002bGao et al, , 2004Yuan et al, 2003;Hwang et al, 2004;van Heerden et al, 2004;Zhao et al, 2004). Since Fe(II) is an important cofactor for these hydroxylases and loosely bound to two histidine sites in these enzymes, non-iron metal ions may decrease the activity of these enzymes by either decreasing cellular iron level or directly replacing iron in the enzymes that hydroxylate HIF.…”